Monday's Molecule #157

 

You need to pay close attention in order to identify this molecule correctly.

Post your answer in the comments. I'll hold off releasing any comments for 24 hours. The first one with the correct answer wins. I will only post correct answers to avoid embarrassment.

There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your comment.)

Some past winners are from distant lands so their chances of taking up my offer of a free lunch are slim. (That's why I can afford to do this!)

In order to win you must post your correct name. Anonymous and pseudoanonymous commenters can't win the free lunch.

Winners will have to contact me by email to arrange a lunch date.

UPDATE: The molecule is L-sedoheptulose 1,7-bisphosphate or L-altro-hept-2-ulose 1,7-bisphosphate. The D isomer is part of the pentose phosphate cycle and the Calvin cycle. The winner is Peter Monaghan.

Winners
Nov. 2009: Jason Oakley, Alex Ling
Oct. 17: Bill Chaney, Roger Fan
Oct. 24: DK
Oct. 31: Joseph C. Somody
Nov. 7: Jason Oakley
Nov. 15: Thomas Ferraro, Vipulan Vigneswaran
Nov. 21: Vipulan Vigneswaran (honorary mention to Raul A. Félix de Sousa)
Nov. 28: Philip Rodger
Dec. 5: 凌嘉誠 (Alex Ling)
Dec. 12: Bill Chaney
Dec. 19: Joseph C. Somody
Jan. 9: Dima Klenchin
Jan. 23: David Schuller

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A Mormon Tale: Ontario to Nauvoo

My wife and our children are cousins of Mitt Romney. This is the story of their common ancestor James Hood and his Mormon descendants.A Mormon Tale

• Glasgow to Ontario
• Ontario to Nauvoo
• Nauvoo to Utah
• The Romney Connection

Ontario to Nauvoo

When we ended the first installment there were two families from Scotland living in Tosorontio township and Nottawasaga Township in southern Ontario. The Hood family and the Hill family came over from Scotland and settled originally in Dalhousie, in eastern Ontario. They moved south in the 1830s.

On April 6, 1832, Alexander Hill (born in 1811 in Scotland) married Agnes Hood (born in 1811 in Scotland). On Feb. 21, 1840, Isabella Hood (born in 1821 in Ontario) married Archibald Newell Hill (born in Scotland). They were married in Tosorontio where the Hill family farms were lcoated. Two brothers married Hood sisters. We are interested in the children of Isabella and Archibald. Recall that Isabella is the sister of William Hood and my wife and children descend from William.

UPDATE: The person in the photo is NOT the Isabella Hood Hill who is the mother of Hannah and the ancestor of Mitt Romney. Instead, it's the daughter of Isabella's sister who married Alexander Hill (see comments).

Archibald Newell Hill and Isobel Hood had two children while living in Canada. Samuel Hood Hill was born in Tosorontio on Dec. 23, 1840. Hannah Hood Hill was born in Tosorontio on July 9, 1842. She died in Colonia Juarez, Mexico in 1929 but a lot of interesting things happened in her life between those dates.

Religion is not on her radar ... and neither is something else

 

Heather Mallick published a column in today's Toronto Star where she declares that she is an atheist [Atheists should make more noise]. Good for her. We need more people to come out of the closet.

Why is she an atheist? It's not because she's opposed to religion it's because religion just isn't "on her radar." She just doesn't care about religion. In this sense she's not much different than most atheists: it's not that they actively study and reject any particular religion, they just don't believe in any gods.

I find it a bit strange that she and her husband ignore religion entirely. That seems like a recipe for disaster since religion is behind a lot of strife in today's world. But that's not what caught my eye when she described the topics that she and her husband do cover. There's seems to be a huge gap ... can you spot it? What else is sitting on the kitchen table?

If you like to stay current, you can’t simultaneously juggle all the elements that make up the news of the world. I follow politics, the arts, memoir and European history, with a minor in Spanish novelists, British comedy and American popular culture. My husband does economics, the history of the English language, meat-based cuisine, the novels of Graham Greene and soccer. The children have assigned themselves music, American fiction, social media and legal issues.

Religion sits on the kitchen table, orphaned.

I still love reading her columns in spite of her obvious deficiency!

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A Mormon Tale: Glasgow to Ontario

My wife and our children are cousins of Mitt Romney. This is the story of their common ancestor James Hood and his Mormon descendants.A Mormon Tale

• Glasgow to Ontario
• Ontario to Nauvoo
• Nauvoo to Utah
• The Romney Connection

Glasgow to OntarioJames Hood was born on April 6, 1776 in Kelso, a small town south of Edinburgh near the border with England. His parent were William Robert Hood (1744-1799)¹ and Hannah Clarke (1752-1832). James had six sisters (Agnes, Isabella, Margaret, Elizabeth, Hannah, and Mary) and one brother Dr. William Hood.

About five years after James was born, the family moved to Bridgeton in Barony Parish . At the time, Bridgeton was a small village, just north of the city of Glasgow. William Hood was employed there as a weaver and it’s quite likely that James also became a weaver at one of the factories in Barony.⁵

James Hood married Elizabeth Jones (1776-1803) in Barony on May 28, 1798. James and Elizabeth were both 22 years old. They had five children: William (1799-1894) (the direct ancestor of my wife and children), Jane (1800-1862), Elizabeth (1801-1875), Hannah (1802-1830), and Jean (1803-1803). Baby Jean dies shortly after birth and her mother, Elizabeth Jones, did not survive birth complications.

Evolution of Horseshoe Crabs

The IDiots are at it again but this time they are aided and abetted by scientists who should know better. The subject is horseshoe crabs, famous as "living fossils" because species that look similar to the four living species were around millions of years ago.

The BBC (United Kingdom) is broadcasting a new television series called "Survivors"¹ staring this month. The first episode is Horseshoe crabs are one of nature’s great survivors. The show is based on a book by Richard Fortey of the Natural History Museum in London, England.

Here's a quotation from the BBC press release where Fortey attempts to explain why horseshoe crabs haven't evolved.

A strange evolution?

Evolution not only brings about ‘improvements’ in body shapes and design that help a species adapt better to its surroundings. It also allows some species to remain basically the same.

‘These creatures tell us that evolution does not move inevitably forwards towards new morphology and new designs,' comments Fortey.

'Evidence for evolution is also found in past designs that endure to the present day. As long as the right habitat endures, then so will some of the creatures that inhabited the distant past.

The Problem With Press Releases

 
Press releases are a problem. Ryan Gregory has found a doozy: Radical Theory Explains the Origin, Evolution, and Nature of Life, Challenges Conventional Wisdom.

You may be tempted to actually read the paper. Don't. First, read what PZ Myers has to say: The comparison to jabberwocky is inevitable.

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Paul Doty (1920 - 2011) and DNA Renaturation

Paul Doty was born in 1920. He died last month (Dec. 5, 2011) at his home in Cambridge, Massachusetts, USA [Paul Mead Doty (1920-2011)]. He was a Professor at Harvard for most of his career.

For many of us, Doty's major contribution to molecular biology was his study of DNA renaturation with his long-time post-doc and collaborator, Julius Marmur (1926 - 1996)¹, a graduate of McGill University in Montréal, Canada. The paper that most of us remember is Marmur and Doty 1962: "Thermal Renaturation of Deoxyribonucleic Acids." This was the first time that the renaturation of complex DNA had been studied in detail and the results have led to many of the common techniques in use today.

Where Is David Attenborough?

 
Jerry Coyne has a little quiz for you as you watch this music video about evolution [An Evolution Music Video]. You should visit his blog website and answer the questions. Sandwalk readers should be able to answer the most difficult question namely, "Figure out where Attenborough is walking at the beginning: it’s a very famous place."

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What's the Difference Between a Human and Chimpanzee?

The number of differences between the human and chimpanzee genomes is consistent with Neutral Theory and fixation by random genetic drift.

How Many Differences?

You can estimate the total number of single nucleotide differences by measuring the rate of hybridization of human and chimpanzee DNA in a technique developed by Dave Kohne and Roy Britten over forty years ago. This technique was applied to human and chimp DNA and the results indicated that the two genomes differed by about 1.5% (reviewed in Britton, 2002). That corresponds to 45 million bp in a genome of 3 billion bp.

This value of 1.5%, rounded up to 2%, gave rise to the widely quoted statement that humans and chimps are 98% identical. Britton (2002) challenged that number by pointing out that humans and chimp genomes differed by a large number of insertions and deletions (indels) that could not have been detected in hybridization studies. He claimed that there was an addition 3.4% of the genome that differed due to indels. That means the the real difference between humans and chimps is closer to 5% and we are only 95% identical!

Much of the difference is due to insertion and deletion of members of gene families. One study shows that the human genome has 689 genes not present in the chimp genome and chimps have 729 genes not present in humans [Mammalian Gene Families: Humans and Chimps Differ by 6%]. That's a total of 1,418 complete genes that are only found in one of the species.

At first glance this looks like 689 completely new genes have evolved in the human lineage since it diverged from our common ancestor with chimpanzees but looks can be deceiving. These genes are members of gene families and all that's happened is that 689 orthologous genes have either arisen by duplication in the human lineage or been lost by deletion in the chimp lineage or 689 new parologous genes have been "born" by gene duplication (or some combination).

Much better date is available today than in 2002 when Britten wrote his paper. We now know by direct comparison that there are at least 30 million single nucleotide differences between human and chimp genomes. There are about 90 million base pair differences as insertion and deletions (Margues-Bonet et al., 2009). The indels (insertions and deletions) may only represent 90,000 mutational events if the average length of an insertion/deletion is 1kb (1000 bp). In fact, more than 75% of indels are less than 5 bp (Britton 2002) so the actual number of mutational events is in the millions. Many of these are undoubtedly due to sequence errors. The latest studies indicate that humans and chimps differ by only 26,500 large indels (>80 bp) (Polavarapu et al., 2011). To a first approximation, the single nucleotide differences are a good measure of the total number of mutational events that have occurred in the two lineages. (underlined portion added on Jan. 25, 2012 - LAM)

Polymorphisms

It's worth noting that many of the differences between the human and chimp genomes are polymorphic within their respective populations. In other words, the variant alleles have not become fixed in the population. This affects the calculations of mutation rate since that calculation assumes that an allele has become fixed in the population by random genetic drift.

The polymorphisms include SNPs, of course, and that's the basis of many studies that look for specific haplotypes associated with disease. At least one of the variants at a given polymorphic locus in humans will be different from the nucleotide in the chimp reference genome. Deletions in the human and chimp genomes can also be polymorphic. Copy number variants (CNVs) in humans have been characterized in a number of studies (Campbell et al. 2011). In terms of total nucleotides, there is more variation in copy number than in single nucleotide polymorphisms (Alkan et al., 2011).

Are the Differences Neutral?

We would like to know if the differences between the human and chimp genomes are neutral alleles or if natural selection has played an important role in fixing these differences. Nobody doubts that many of the changes we see are adaptive in one or other of the lineages but can we recognize those important adaptive changes in a sea of possible neutral changes?

Several lines of evidence suggest that most of the changes are non-adaptive. First, since most (~90%) of the genome is junk, and most of the differences are located in junk DNA, it follows that most of the new alleles had no effect on function.

Second, if we look at the pattern of changes this is what we see for one of the human chromosomes.

The percent identity between humans and chimps fluctuates between 98% and 99% identity and the differences are pretty evenly scattered throughout chromosome 7. Remember, most of that DNA is junk.

Calculating the rate of evolution in terms of nucleotide substitutions seems to give a value so high that many of the mutations must be neutral ones.

Motoo Kimura (1968)The third line of evidence has to do with the mutation rate and fixation in the two lineages. The mutation rate in humans is about 130 mutations per generation based on our knowledge of the biochemistry of DNA replication [Mutation Rates]. A value that's consistent with recent direct measurements [Human Y Chromosome Mutation Rates] [Direct Measurement of Human Mutation Rate]. Michael Lynch (2010) bases his estimate of human mutation rates on a number of other studies. He comes up with a value of about 80 new mutations per generation.

In an evolving population the rate of fixation of neutral alleles is equal to the mutation rate [Random Genetic Drift and Population Size]. How many mutations would we expect in the human lineage since it diverged from a common ancestor with chimpanzees if all of the fixed alleles were neutral? The two species diverged about 5 million years ago. The average generation time in the human lineage is about ten years, so that means 500,000 generations. If the rate of mutation is about 100 new mutations per generation, then we would expect to see about 50 million new mutations in the human lineage. The actual number is about 22.5 million (half of 45 million). We're certainly in the right ballpark.

The actual mutation rate may be lower than we calculate.

We're certainly safe in concluding that the number of differences between humans and chimps is consistent with Neutral Theory and we should accept this as the null hypothesis.

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Alkan C, Coe BP, Eichler EE. (2011) Genome structural variation discovery and genotyping. Nat Rev Genet. 12:363-376. [PubMed]

Britton, R.J. (2002) Divergence between samples of chimpanzee and human DNA sequences if 5%, counting indels. Proc. Natl. Acad. Sci. (USA) 99:13633-13636.

Campbell, C.D., Sampas, N., Tsalenko, A., Sudmant, P.H., Kidd, J.M., Malig, M., Vu, T.H., Vives, L., Tsang, P., Bruhn, L., and Eichler, E.E. (2011) Population-genetic properties of differentiated human copy-number polymorphisms. Am J Hum Genet. 88:317-32. [PubMed]

Marques-Bonet, T., Ryder, O.A., and Eichler, E.E. (2009) Sequencing primate genomes: what have we learned? Annu. Rev. Genomics Hum. Genet. 10:355-386. [PubMed]

Lynch, M. (2010) Rate, molecular spectrum, and consequences of human mutation. Proc. Natl. Acad. Sci. (USA) 107:961-968. [PubMed]

Polavarapu, N., Arora, G., Mittal, V.K., McDonald, J.F. (2011) Characterization and potential functional significance of human-chimpanzee large INDEL variation. Mob. DNA 2:13. [PubMed] [doi:10.1186/1759-8753-2-13]

Monday's Molecule #156

 

This is one of the most important molecules on Earth. Without it we wouldn't be around and neither would most species. The revised structure is shown here. The one shown in the textbooks is wrong and this includes my own recently published edition of Principles of Biochemistry. Oops!

You need to identify the molecule, including the part with the white carbon atoms. You also need to specify how this molecule differs from the one shown in most textbooks.

Post your answer in the comments. I'll hold off releasing any comments for 24 hours. The first one with the correct answer wins. I will only post correct answers to avoid embarrassment.

There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your comment.)

Some past winners are from distant lands so their chances of taking up my offer of a free lunch are slim. (That's why I can afford to do this!)

In order to win you must post your correct name. Anonymous and pseudoanonymous commenters can't win the free lunch.

Winners will have to contact me by email to arrange a lunch date.

UPDATE: The molecule is the iron-sulfur-molydenum cluster with bound homocitrate. The central atom was thought to be nitrogen but recent work has shown that it is most likely carbon. The cluster is in the active site of bacterial nitrogenase, an enzyme responsible for fixing atmospheric nitrogen and converting it to ammonia. This is a key part of the nitrogen cycle. The winner is David J. Schuller. I don't know if he will come for lunch.

Winners
Nov. 2009: Jason Oakley, Alex Ling
Oct. 17: Bill Chaney, Roger Fan
Oct. 24: DK
Oct. 31: Joseph C. Somody
Nov. 7: Jason Oakley
Nov. 15: Thomas Ferraro, Vipulan Vigneswaran
Nov. 21: Vipulan Vigneswaran (honorary mention to Raul A. Félix de Sousa)
Nov. 28: Philip Rodger
Dec. 5: 凌嘉誠 (Alex Ling)
Dec. 12: Bill Chaney
Dec. 19: Joseph C. Somody
Jan. 9: Dima Klenchin

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The Modern Molecular Clock

The first molecular phylogenetic trees were constructed from the amino acid sequences of small proteins. One of those proteins was cytochrome c and it turned out to be very useful because homologues could be found in all species, including bacteria.

The original trees were published by Emanual Margoliash but I'm showing a later version here from Fitch and Margoliash (1967). This is a very famous tree that's found in many textbooks. (The version shown here is from Mulligan (2008).)

From the very beginning, the authors of these molecular phylogenetic trees noted that the rate of change in each lineage was approximately constant. You can see that in the tree shown here. The number of changes in the lineage leading to yeast (Saccharomyces) is 17+10+2=31 from the common root. The number of changes in the lineage leading to insects is 31 or 28, depending on the species. The number leading to humans and monkeys is 32.

Margoliash on "Homology" (1969)

Emanuel Margoliash (1920 - 2008) is famous for his studies of the evolution of cytochrome c genes/proteins. His lab sequenced dozens of them and he published some of the first molecular phylogenetic tress back in the early 1960s.

I recently stumbled on a letter he published in Science back in 1969 (Margoliash, 1969). It's about how you define "homology." This is one of my pet peeves. I've been trying to teach people for years that homology refers to the fact that two genes share a common ancestor. It a conclusion based on evidence such as sequence similarity. For example, if two genes/proteins are more than 30% identical over their entire length then you can conclude that they are homologous—they descend from a common ancestor. The conclusion is based on evidence, such as 30% sequence identity. Don't confuse "similarity" and "homology" because they are two different things.¹

Homology is like being pregnant. Either you are or you aren't. You can't be 30% pregnant and you can't be 30% homologous.

I knew that the definition of homology had changed over the years but I didn't know that the dispute over its usage in molecular phylogeny started in the 1960s. Here's the Margoliash letter.

I regret the error in citation (the journal name was given as Nature, rather than Science), which crept in among the 462 references of the review (1) to which Winter, Walsh, and Neurath take exception (Letters, 27 Dec.). In that review, the term homologous was taken to imply, in parallel to universal biological usage, "that the genes coding for the polypeptide chains considered, in all the species carrying these proteins, had at one time a common ancestral gene," and we stated that when this concept is not intended "it would be best to use any of the numerous synonyms of 'similar' and 'similarity' and not appear to be prejudging the issue of evolutionary relations." The "pointed and specific criticism" followed, and was entirely contained in the sentence: "Other definitions may cause confusion and are unlikely to supplant well established biological usages." The "other definitions" referred to the article by Neurath, Walsh, and Winter (2), in which they state, "The term homology as applied to proteins refers to similarity in amino acid sequence," and later, that comparisons of protein structures "must be interpreted on a statistical basis lest we misinterpret random similarities."

On this last score there is no argument. Winter, Walsh, and Neurath will surely agree that in this field erroneous conclusions are likely to arise from the lack of an appropriate statistical distinction between random similarities and similarities of structure greater than can result from random phenomena. An excellent method of performing just such a distinction was published by Fitch (3), and although Neurath, Walsh, and Winter acknowledge it in their article (2), they do not use any acceptable statistical techniques in their comparisons of proteases. Thus, even by their own definition they fail to show "homology."

Homology, in any biological evolutionary context has a generally understood and well-defined meaning, namely the one we have adopted for use in protein primary structure comparisons. One cannot argue that such comparisons represent an area of knowledge separate from evolutionary biology, and that therefore one may use the same words for other meanings, since such protein studies obtain their interest largely in terms of evolutionary concepts and have their major impact in the taxonomic-evolutionary field. Winter, Walsh, and Neurath justify their novel definition of "homology" by maintaining that, without fossil remains, it is not possible to decide whether the structural genes corresponding to a set of present-day proteins are or are not ancestrally related. Apart from the inherent danger of assuming that a problem is insoluble, it may be pointed out that six pages after the definition of "homology," the paper (1) reviewed a statistical method for demonstrating just such ancestral homology. One requires enough primary structures to derive a "statistical phylogenetic tree," as has been possible in the case of cytochrome c (4). From such a tree a simple statistical calculation permits one to approximate the number of residues in a set of proteins that will remain invariant, because of biological necessity, no matter how many species are examined (5). If, in the comparison of any two proteins of this set, the number of identical residues is substantially in excess of the number that remain invariant in the entire set of proteins, then clearly this excess cannot result from functional convergence from different phylogenetic origins, a process yielding analogous structures, and, therefore, it can only be attributed to ancestral homology. In such a procedure, the assumption of the constancy of the genetic code has replaced the fossils of the morphological evolutionist.

Even if one does not accept the validity of such a demonstration, it is difficult to understand why there is an insistence on using the word "homology" for "similarities of protein primary structure greater than random." Any of the over 30 synonyms of "similarity" (6) or a variety of elegant neologisms would do, and prevent an insidious misunderstanding likely to arise in biological literature. Rather than take Alice in her confused trip in Wonderland as a model for logical scientific nomenclature, I prefer to follow the 17th-century poet reacting against a form of debasement of the language then prevalent, and "call a cat a cat" (7).

E. MARGOLIASH
Department of Molecular Biology,
Abbott Laboratories,
North Chicago, Illinois 60064
References

1. C. Nolan and E. Margoliash, Ann. Rev. Biochem. 37, 727 (1968).
2. H. Neurath, K. A. Walsh, W. P. Winter, Science 158, 1638 (1967).
3. W. M. Fitch, J. Mol. Biol. 16, 9 (1966).
4. W. M. Fitch and E. Margoliash, Science 155, 279 (1967).
5. W. M. Fitch and E. Margoliash, Biochem. Genet. 1, 65 (1967).
6. Roget's Thesaurus (St. Martin's Press, New York, 1965).
7. N. Boileau, Satires 1, line 52 (1660). "J'appelle un chat un chat, et Rolet un fripon."

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1. Very few people pay attention to me. I appear to be fighting for a lost cause.

Margoliash, E. (1969) Homology: A Definition. Science 163:127

Understanding Mutation Rates and Evolution

The recent article by physician Joseph A. Kuhn contains a lot of errors and misunderstandings [Physicians Can Be IDiots]. Today I want to focus on one paragraph.

The complexity of creating two sequential or simultaneous mutations that would confer improved survival has been studied in the malaria parasite when exposed to chloroquine. The actual incidence of two base-pair mutations leading to two changed amino acids leading to resistance has been shown to be 1 in 10²⁰ cases (42). To better understand this incidence, the likelihood that Homo sapiens would achieve any single mutation of the kind required for malaria to become resistant to chloroquine (a simple shift of two amino acids) would be 100 million times 10 million years (many times the age of the universe). This example has been used to further explain the difficulty in managing more than one mutation to achieve benefit.

The reference is to The Edge of Evolution by Michael Behe. His book was published in 2007 but I never got around to reviewing it thoroughly—partly because it's so difficult to explain where he goes wrong.¹ Here's my take on one part of the book: The Two Binding Sites Rule. This post covers "chloroquine-complexity clusters" (CCC).

Congratulations Vip!

 

Here's Vipulan Vigneswaran with his fabulous Biochemistry textbook that he won by contributing to Monday's Molecule [And the Winner Is ...]. Vip is studying Chemistry at the University of Toronto.

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Alain de Botton Tells Us the Good Things About Religion

 
Here's a TED talk by Alain de Botton. He claims to be an atheist but he's promoting Atheism 2.0. That's a version of atheism that incorporates all the good parts of religion like how they can brainwash children and con people out of lots of money. And pilgrimage. Let's not forget the value of pilgrimage and the importance of travel. (Think Canterbury Tales!)

There's a certain mysticism about TED talks that I deplore. In order to be a successful TED talker you need to be articulate and clever. You need to be engaging and just a little bit radical—though not too radical. That's just about all it takes to get an enthusiastic standing ovation from the people who comes to listen to these 18 talks. What you're actually saying doesn't really count for anything as this example plainly shows.

The mantra of TED talks is "Ideas Worth Spreading" but if you think about it there aren't very many important new ideas that can be explained in 18 minutes. On the other hand, if you want to spread ideas that your audience already agrees with then TED talks are just the thing for you.

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[Hat Tip: PZ Myers: Alain de Botton is right about one thing.]